US5077277A - Chemical derivatives of antibiotics ll-e19020 alpha and beta - Google Patents

Chemical derivatives of antibiotics ll-e19020 alpha and beta Download PDF

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Publication number
US5077277A
US5077277A US07/403,232 US40323289A US5077277A US 5077277 A US5077277 A US 5077277A US 40323289 A US40323289 A US 40323289A US 5077277 A US5077277 A US 5077277A
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magnetic resonance
resonance spectrum
nuclear magnetic
characteristic
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Douglas W. Phillipson
Guy T. Carter
Donald B. Borders
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Roche Vitamins Inc
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American Cyanamid Co
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Assigned to AMERICAN CYANAMID COMPANY reassignment AMERICAN CYANAMID COMPANY ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: PHILLIPSON, DOUGLAS WAYNE, BORDERS, DONALD BRUCE, CARTER, GUY THOMAS
Priority to US07/403,232 priority Critical patent/US5077277A/en
Priority to AT90115468T priority patent/ATE131487T1/de
Priority to DE69024141T priority patent/DE69024141T2/de
Priority to ES90115468T priority patent/ES2082806T3/es
Priority to DK90115468.2T priority patent/DK0416327T3/da
Priority to EP90115468A priority patent/EP0416327B1/fr
Priority to CA002024497A priority patent/CA2024497C/fr
Priority to AU62154/90A priority patent/AU637137B2/en
Priority to KR1019900013944A priority patent/KR0158692B1/ko
Priority to JP2232606A priority patent/JP3053205B2/ja
Publication of US5077277A publication Critical patent/US5077277A/en
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Assigned to HOFFMANN-LA ROCHE INC. reassignment HOFFMANN-LA ROCHE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AMERICAN CYANAMID COMPANY
Priority to GR950403726T priority patent/GR3018581T3/el
Assigned to ROCHE VITAMINS INC. reassignment ROCHE VITAMINS INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HOFFMANN-LA ROCHE INC.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/02—Acyclic radicals

Definitions

  • This invention relates to novel antibacterial compounds and to the treatment of bacterial infections in animals in need of such treatment.
  • the antibiotics LL-E19020 ⁇ and ⁇ are disclosed and claimed by physical/chemical characteristics in U.S. Pat. No. 4,705,688, the contents of which are hereby incorporated by reference.
  • These antibiotics derived from the microorganism streptomyces lydicus subspecies tanzanius NRRL 18036, are active as antibacterial agents. They are also growth promoters, anti-protozoan agents, and anthelmintic agents.
  • Phenelfamycins Another complex of antibiotics named Phenelfamycins has been disclosed by Abbott Laboratories, Abbott Park, Ill. at the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy, New York, NY in October, 1987.
  • An object of the present invention is to provide chemical derivatives of the antibiotics LL-E19020 ⁇ and LL-E19020 ⁇ which also have activity as antibacterial agents.
  • this invention is concerned with chemically prepared derivatives of LL-E19020 ⁇ and ⁇ which are also antimicrobial agents and which are described below by their structures and physical/-chemical characteristics together with methods for their preparation.
  • the ammonolysis product of LL-E19020 ⁇ and ⁇ has ultraviolet absorption spectra as shown in FIG. I; an infrared absorption spectrum as shown in FIG. II; a proton magnetic resonance spectrum as shown in FIG. III; and a carbon-13-nuclear magnetic resonance spectrum as shown in FIG. IV.
  • the ammonolysis product of LL-E19020 ⁇ and ⁇ is prepared by dissolving LL-E19020 ⁇ or ⁇ in acetonitrile, reacting with ammonium hydroxide for 12-24 hours, diluting with water and acidifying with hydrochloric acid to pH 1. This solution is extracted into ethyl acetate, evaporated and then purified by chromatography.
  • the methyl ester of LL-E19020 ⁇ has a proton magnetic resonance spectrum as shown in FIG. V.
  • methyl esters of LL-E9020 ⁇ and ⁇ are prepared by dissolving either LL-E19020 ⁇ or ⁇ in a solvent such as ethyl acetate, acetonitrile or dichloromethane, or mixtures thereof, followed by reaction with ethereal diazomethane and purification by chromatography.
  • a solvent such as ethyl acetate, acetonitrile or dichloromethane, or mixtures thereof
  • the monosaccharide of the methyl ester of LL-E19020 ⁇ has an infrared spectrum as shown in FIG. VI; a proton magnetic resonance spectrum as shown in FIG. VII; and a carbon-13-magnetic resonance spectrum as shown in FIG. VIII.
  • the monosaccharide of the methyl esters of LL-E19020 ⁇ and ⁇ are prepared by dissolving the methyl ester of LL-E19020 ⁇ or ⁇ in methanol, cooling to 0° C. and reacting with dilute hydrochloric acid in methanol for several hours, followed by dilution with water, extraction into ethyl acetate and purification by chromatography.
  • the aglycone of the methyl ester of LL-E19020 ⁇ has ultraviolet absorption spectra as shown in FIG. IX; an infrared absorption spectrum as shown in FIG. X; a proton magnetic resonance spectrum as shown in FIG. XI; and a carbon-13-nuclear magnetic resonance spectrum as shown in FIG. XII.
  • the aglycone of the methyl ester of LL-E19020 ⁇ has ultraviolet absorption spectra as shown in FIG. XIII; an infrared absorption spectrum as shown in FIG. XIV; a proton magnetic resonance spectrum as shown in FIG. XV; and a carbon-13-magnetic resonance spectrum as shown in FIG. XVI.
  • the aglycone of the methyl esters of LL-E19020 ⁇ and ⁇ are prepared by reacting the methyl ester of LL-E19020 ⁇ or ⁇ with hydrochloric acid in methanol at reduced temperature for several hours, followed by extraction into ethyl acetate and chromatographic purification.
  • the triacetate of the aglycone methyl ester of LL-E19020 ⁇ has an infrared absorption spectrum as shown in FIG. XVII; a proton magnetic resonance spectrum as shown in FIG. XVIII; and a carbon-13-nuclear magnetic resonance spectrum as shown in FIG. XIX.
  • the triacetate of the aglycone methyl ester of LL-E19020 ⁇ has a proton magnetic resonance spectrum as shown in FIG. XX; and a carbon-13-nuclear magnetic resonance spectrum as shown in FIG. XXI.
  • the triacetate of the aglycone methyl ester of LL-E19020 ⁇ and ⁇ is prepared by reacting the aglycone methyl ester of LL-E19020 ⁇ or ⁇ with a solution of 4-dimethylamino pyridine and acetic anhydride in dichloromethane for several hours followed by purification by chromatography.
  • FIG. I is an ultraviolet absorption spectrum of the ammonolysis product in acidic, basic and alcoholic solutions
  • FIG. II is an infrared absorption spectrum of the ammonolysis product of LL-E19020 ⁇ dispersed in potassium bromide;
  • FIG. III is a proton magnetic resonance spectrum of the ammonolysis product
  • FIG. IV is a carbon-13-nuclear magnetic resonance print-out of the ammonolysis product of LL-E19020 ⁇ ;
  • FIG. V is a proton magnetic resonance spectrum of the methyl ester of LL-E19020 ⁇
  • FIG. VI is an infrared absorption spectrum of the monosaccharide of the methyl ester of LL-E19020 ⁇ dispersed in potassium bromide;
  • FIG. VII is a print-out of the proton magnetic spectrum of the monosaccharide of the methyl ester of LL-E19020 ⁇ ;
  • FIG. VIII is a print-out of the carbon-13-magnetic resonance spectrum of the monosacchoride of the methyl ester of LL-E19020 ⁇ ;
  • FIG. IX is an ultraviolet absorption spectrum of the aglycone of the methyl ester of LL-E19020 ⁇ ;
  • FIG. X is an infrared absorption spectrum of the aglycone of the methyl ester of LL-E19020 ⁇ in potassium bromide;
  • FIG. XI is a proton magnetic resonance spectrum print-out of the aglycone of the methyl ester of LL-E19020 ⁇ ;
  • FIG. XII is a carbon-13-nuclear magnetic resonance spectrum of the aglycone of the methyl ester of LL-E19020 ⁇ ;
  • FIG. XIII is the ultraviolet absorption spectrum of the aglycone of the methyl ester of LL-E19020 ⁇ ;
  • FIG. XIV is the infrared absorption spectrum of the aglycone of the methyl ester of LL-E19020 ⁇ in potassium bromide;
  • FIG. XV is the proton magnetic resonance spectrum of the aglycone of the methyl ester of LL-E19020 ⁇ ;
  • FIG. XVI is the carbon-13-nuclear magnetic resonance spectrum of the aglycone of the methyl ester of LL-E19020 ⁇ ;
  • FIG. XVII is the infrared absorption spectrum of the triacetate of the aglycone methyl ester of LL-E19020 ⁇ in potassium bromide;
  • FIG. XVIII is the proton magnetic resonance spectrum of the triacetate of the aglycone methyl ester of LL-E19020 ⁇ ;
  • FIG. XIX is the carbon-13-nuclear magnetic resonance spectrum of the triacetate of the aglycone methyl ester of LL-E19020 ⁇ ;
  • FIG. XX is the proton magnetic resonance spectrum of the triacetate of the aglycone methyl ester of LL-E19020 ⁇ ;
  • FIG. XXI is the carbon-13-nuclear magnetic resonance spectrum of the triacetate of the aglycone methyl ester of LL-E19020 ⁇ .
  • the in vitro antibacterial activity of these compounds was determined against a spectrum of gram-positive and gram-negative bacteria and anaerobes by a standard agar dilution method.
  • Mueller-Hinton agar containing 5% sheep blood or Wilkins Chalgren agar and two-fold decreasing concentrations of the test compounds were poured into petri dishes.
  • the agar surfaces were inoculated with 1 to 5 ⁇ 10 4 colony forming units of bacteria by means of the Steers replicating device.
  • the lowest concentration of antibiotic that inhibited growth of a bacterial strain after 18 hours incubation was recorded as the minimal inhibitory concentration (MIC) for that strain.
  • MIC minimal inhibitory concentration
  • Compound I Ammonolysis Product of LL-E19020 ⁇ and ⁇ .
  • the compounds of this invention find utility in the suppression of bacterial infections and as general disinfectants for laboratories.
  • they may be administered in the form of conventional pharmaceutical or veterinary compositions appropriate for the intended use.
  • Such compositions may be formulated so as to be suitable for oral, parenteral, or topical administration.
  • the active compounds may be combined in admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms, depending on the form of preparation desired for administration, i.e., oral, parenteral or topical.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Communicable Diseases (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
US07/403,232 1989-09-05 1989-09-05 Chemical derivatives of antibiotics ll-e19020 alpha and beta Expired - Fee Related US5077277A (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
US07/403,232 US5077277A (en) 1989-09-05 1989-09-05 Chemical derivatives of antibiotics ll-e19020 alpha and beta
AT90115468T ATE131487T1 (de) 1989-09-05 1990-08-10 Chemische derivate von antbiotika ll-e19020 alpha und beta
DE69024141T DE69024141T2 (de) 1989-09-05 1990-08-10 Chemische Derivate von Antbiotika LL-E19020 alpha und beta
ES90115468T ES2082806T3 (es) 1989-09-05 1990-08-10 Derivados quimicos de los antibioticos alfa- y beta-ll-e19020.
DK90115468.2T DK0416327T3 (da) 1989-09-05 1990-08-10 Kemiske derivater af antibiotika LL-E19020alfa og -beta
EP90115468A EP0416327B1 (fr) 1989-09-05 1990-08-10 Dérivés chimiques des antibiotiques LL-E19020 alpha et bêta
CA002024497A CA2024497C (fr) 1989-09-05 1990-08-31 Derives chimiques des antibiotiques ll-f19020 alpha et beta
AU62154/90A AU637137B2 (en) 1989-09-05 1990-09-04 Chemical derivatives of antibiotics ll-f19020 alpha and beta
KR1019900013944A KR0158692B1 (ko) 1989-09-05 1990-09-04 항생물질 ll-e19020 알파 및 베타의 화학적 유도체
JP2232606A JP3053205B2 (ja) 1989-09-05 1990-09-04 抗生物質ｌｌ―ｅ１９０２０アルファおよびベータの化学的誘導体
GR950403726T GR3018581T3 (en) 1989-09-05 1995-12-29 Chemical derivatives of antibiotics LL-E19020 alpha and beta

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US07/403,232 US5077277A (en) 1989-09-05 1989-09-05 Chemical derivatives of antibiotics ll-e19020 alpha and beta

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EP (1) EP0416327B1 (fr)
JP (1) JP3053205B2 (fr)
KR (1) KR0158692B1 (fr)
AT (1) ATE131487T1 (fr)
AU (1) AU637137B2 (fr)
CA (1) CA2024497C (fr)
DE (1) DE69024141T2 (fr)
DK (1) DK0416327T3 (fr)
ES (1) ES2082806T3 (fr)
GR (1) GR3018581T3 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5188945A (en) * 1991-09-09 1993-02-23 American Cyanamid Company Recovery process for antibiotics ll-e19020 alpha and beta
US5814613A (en) * 1991-09-09 1998-09-29 Roche Vitamins Inc. Antibiotic LL-E19020 gamma

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993013217A1 (fr) * 1991-12-27 1993-07-08 Gruppo Lepetit S.P.A. Antibiotique ge 21640a

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4704276A (en) * 1986-06-30 1987-11-03 American Cyanamid Company Compositions and methods for increasing the growth rate of meat producing animals, improving the efficiency of feed utilization thereby and enhancing lactation in lactating ruminants
US4705688A (en) * 1986-06-30 1987-11-10 American Cyanamid Company Antibiotic LL-E19020 α and β
US4705680A (en) * 1986-01-22 1987-11-10 Colgate-Palmolive Company Stable dental cream in polyethylene or polypropylene container
US4753798A (en) * 1986-06-30 1988-06-28 American Cyanamid Company Methods and compositions for controlling protozoal infections in warm-blooded animals

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3778225D1 (de) * 1986-06-30 1992-05-21 American Cyanamid Co Antibiotikum ll-e19020 alpha und beta.
CA1267514A (fr) * 1987-07-15 1990-04-10 Jobst Ulrich Gellert Buse d'injection a revetement pour le moulage
FR2620953B1 (fr) * 1987-09-28 1990-04-20 Seymarc Alain Buse d'injection de type modulaire, notamment pour injecter des matieres plastiques
DE9002048U1 (de) * 1990-02-21 1990-04-19 SFR-Formenbau Dangelmaier GmbH, 7410 Reutlingen Beheizte Düse, sogenannte Langdüse für ein Kunststoff-Spritzgießwerkzeug

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4705680A (en) * 1986-01-22 1987-11-10 Colgate-Palmolive Company Stable dental cream in polyethylene or polypropylene container
US4704276A (en) * 1986-06-30 1987-11-03 American Cyanamid Company Compositions and methods for increasing the growth rate of meat producing animals, improving the efficiency of feed utilization thereby and enhancing lactation in lactating ruminants
US4705688A (en) * 1986-06-30 1987-11-10 American Cyanamid Company Antibiotic LL-E19020 α and β
US4753798A (en) * 1986-06-30 1988-06-28 American Cyanamid Company Methods and compositions for controlling protozoal infections in warm-blooded animals

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5188945A (en) * 1991-09-09 1993-02-23 American Cyanamid Company Recovery process for antibiotics ll-e19020 alpha and beta
US5814613A (en) * 1991-09-09 1998-09-29 Roche Vitamins Inc. Antibiotic LL-E19020 gamma

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Publication number Publication date
AU637137B2 (en) 1993-05-20
CA2024497A1 (fr) 1991-03-06
GR3018581T3 (en) 1996-03-31
EP0416327B1 (fr) 1995-12-13
DE69024141D1 (de) 1996-01-25
AU6215490A (en) 1991-03-14
JP3053205B2 (ja) 2000-06-19
DK0416327T3 (da) 1996-01-22
CA2024497C (fr) 2000-10-24
DE69024141T2 (de) 1996-08-01
EP0416327A3 (en) 1991-08-07
EP0416327A2 (fr) 1991-03-13
JPH03130298A (ja) 1991-06-04
KR910006314A (ko) 1991-04-27
ES2082806T3 (es) 1996-04-01
ATE131487T1 (de) 1995-12-15
KR0158692B1 (ko) 1998-11-16

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